In the context of skeletal tissue repair, Regenerative Medicine (TM) is the local application of adult stem cells to promote reconstruction of tissue defects. The objective of Regenerative Medicine (TM) is to deliver a high density of repair-competent cells to the defect site in a format that optimizes both the initial healing process and the subsequent tissue integration and remodeling. Osiris Therapeutics, Inc. is engaged in the development of cellular transplants and cell-matrix products for the treatment of connective tissue disorders. These cellular transplants and cell- matrix products are derived from Mesenchymal Stem Cells (MSCs), the progenitor cells that give rise to all mesenchymal tissues such as bone, cartilage, tendon, muscle, fat and bone marrow. Previous pre-clinical animal studies by Osiris scientists have established the efficacy of autologous MSCs to heal large bone defects. In the current proposal, we intend to test whether by using MSCs that have been pre-directed into the osteogenic lineage, we can optimize the regenerative process to accelerate and enhance bone formation over that achieved by implantation of undifferentiated MSCs. This Phase I proposal is designed to determine the parameters governing osteogenic human MSC-based implants that lead to the optimal regeneration of clinically significant bone defects. PROPOSED COMMERCIAL APPLICATION: The development of a commercially available cell-based bone graft substitute, with enhanced and accelerated healing potential, will have a beneficial impact on the treatment of patients requiring bone augmentation of clinical settings such as a spine fusion, treatment of non-unions and cysts, prosthetic implant fixation, and craniofacial reconstruction.